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1.
Lancet Haematol ; 10(1): e24-e34, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36402146

ABSTRACT

BACKGROUND: Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy. METHODS: We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 µg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing. FINDINGS: Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 [23%] had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six [10%] had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 [37%] patients), increased amylase or lipase concentration (five [8%] patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four [7%] patients), pain (four [7%] patients), and hypertension (four [7%] patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed. INTERPRETATION: The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response. FUNDING: Takeda Oncology and Amgen.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Male , Humans , Female , Adult , Middle Aged , Aged , Philadelphia Chromosome , Blast Crisis/drug therapy , Blast Crisis/etiology , Alanine Transaminase/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects
2.
Hematology ; 26(1): 88-95, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34000978

ABSTRACT

Objectives: Reactive oxygen species (ROS) are under scrutiny as a participant in the pathophysiology of myelodysplastic syndrome (MDS) and the progression of MDS to acute myeloid leukemia (AML). Measurement of intracellular ROS (iROS) is particularly important since iROS is a direct indicator of cellular health and integrity.Methods: We developed a technique to measure standardize iROS (siROS) level in lymphocytes and bone marrow (BM) CD34+ hematopoietic progenitors using the fluorescent probe dichlorofluorescein (DCF). We then quantified the siROS in 38 consecutive BM specimens from 27 MDS patients over the course of 10 months. Disease outcome of these patients were also assessed.Results: High serum ferritin, high blast count and poor IPSS were associated with inferior survival and AML progression in this cohort. High blast MDS patients had lower siROS in their BM CD34+ cells than those of low blast patients, consistent with increased reliance on glycolysis and enhanced ROS defense in high blast MDS. We also observed narrower siROS distribution in the BM CD34+ cells of high blast patients, suggesting that loss of heterogeneity in ROS content accompanies the clonal evolution of MDS. Furthermore, we observed a strong correlation between CD34+ cells siROS and serum ferritin level in high blast patients. In one case, iron chelation therapy (ICT) resulted in parallel decreases in serum ferritin and CD34+ cells siROS.Conclusion: Our findings established the siROS profile in early hematopoietic cells of MDS patients and its relationship with blast count and iron overload.


Subject(s)
Blast Crisis/metabolism , Hematopoietic Stem Cells/metabolism , Iron Overload/metabolism , Leukemia, Myeloid, Acute/metabolism , Myelodysplastic Syndromes/metabolism , Aged , Aged, 80 and over , Blast Crisis/etiology , Blast Crisis/pathology , Blast Crisis/therapy , Female , Hematopoietic Stem Cells/pathology , Humans , Iron Overload/complications , Iron Overload/therapy , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/therapy
3.
Pan Afr Med J ; 36: 142, 2020.
Article in English | MEDLINE | ID: mdl-32874406

ABSTRACT

Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome t (9;22) and the BCR-ABL fusion gene. The condition is relatively rare, accounting for 2.0% to 3.0% of childhood leukemia cases. CML has historically been a triphasic disease. Most patients are diagnosed in chronic phase. Without treatment, it inevitably progresses into a more aggressive accelerated phase and blast crisis. Some proportion of CML cases of blastic transformation develop an extramedullary disease that involves rarely central nervous system. This report describe an extremely rare case of 13-year-old girl with CML and extramedullary blast crisis in the central nervous system. Treatment options and monitoring of disease response are discussed.


Subject(s)
Blast Crisis/diagnosis , Central Nervous System/pathology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemic Infiltration/diagnosis , Adolescent , Algeria , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blast Crisis/etiology , Blast Crisis/pathology , Central Nervous System/diagnostic imaging , Female , Humans , Imatinib Mesylate/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemic Infiltration/drug therapy , Leukemic Infiltration/pathology , Recurrence
5.
Leuk Lymphoma ; 60(5): 1136-1145, 2019 05.
Article in English | MEDLINE | ID: mdl-30301399

ABSTRACT

It is controversial whether acute myeloid leukemia (AML) patients with 20-29% bone marrow (BM) blasts should be considered AML or myelodysplastic syndromes (MDS). We retrospectively studied 382 patients, including 108 AML with 20-29% BM blasts (AML20-29), 210 AML with ≥30% BM blasts (AML ≥ 30), and 64 MDS with 10-19% BM blasts (MDS-EB2). We found that AML20-29 were more similar to MDS-EB2 in terms of advanced age, less blood count, the increased presence of poor-risk cytogenetics. The frequency of mutated genes in AML20-29 had both the characters of AML and MDS. Median overall survival of AML20-29 and MDS-EB2 were similar and shorter than those of AML ≥ 30 (p = .045). Multivariate analysis showed inferior survival with increased age, low platelet count and FLT3 mutations. Our findings suggest that AML20-29 have clinical features more similar to MDS than AML.


Subject(s)
Bone Marrow/pathology , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/etiology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Blast Crisis/diagnosis , Blast Crisis/etiology , Blast Crisis/therapy , Disease Management , Disease Progression , Disease Susceptibility , Female , Gene Frequency , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Mutation , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/pathology , Prognosis
6.
J Med Case Rep ; 12(1): 257, 2018 Sep 10.
Article in English | MEDLINE | ID: mdl-30196795

ABSTRACT

BACKGROUND: Patients with chronic myeloid leukemia typically present with high white blood cell counts revealed during annual checkups. Leukemic arthritis and hypercalcemia are rare manifestations in patients with chronic myeloid leukemia. CASE PRESENTATION: A 35-year-old Thai man who had been diagnosed with chronic myeloid leukemia in the chronic phase developed blast crisis while he was receiving ongoing treatment with imatinib at 400 mg/day. Initially, he presented with oligoarthritis in both knees and ankles. A bone scintigraphy showed a prominent bony uptake, with a symmetrical, increased uptake in many bone areas. Induction therapy with a 7 + 3 induction regimen was prescribed in conjunction with 600 mg of imatinib once daily before switching to 140 mg of dasatinib. He subsequently developed severe hypercalcemia (total serum calcium of 17.8 mg/dL), with generalized osteolytic lesions detected on a bone survey. His serum vitamin D level was 50.64 ng/mL, while the serum parathyroid hormone level was 9.82 pg/mL. Despite the administration of an aggressive intravenously administered hydration, intravenously administered calcitonin, and 600 mg/day of imatinib, the severe hypercalcemia was refractory. We therefore decided to prescribe 20 mg/day of intravenously administered dexamethasone; fortunately, his serum calcium level decreased dramatically to normal range within a few days. CONCLUSIONS: Although leukemic arthritis and severe hypercalcemia are extraordinary presentations in patients with chronic myeloid leukemia, the advanced phase of the disease might bring on these symptoms. Apart from parathyroid hormone-related protein-related hypercalcemia, vitamin D is a mechanism of humoral-mediated hypercalcemia.


Subject(s)
Arthritis/etiology , Hypercalcemia/etiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adult , Antineoplastic Agents/adverse effects , Arthritis/blood , Arthritis/chemically induced , Arthritis/therapy , Blast Crisis/chemically induced , Blast Crisis/drug therapy , Blast Crisis/etiology , Humans , Hypercalcemia/blood , Hypercalcemia/chemically induced , Hypercalcemia/therapy , Imatinib Mesylate/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Male
7.
Emerg Med Clin North Am ; 36(3): 603-608, 2018 Aug.
Article in English | MEDLINE | ID: mdl-30037446

ABSTRACT

Emergency providers are likely to encounter patients with acute and chronic leukemias. In some cases, the first presentation to the emergency department may be for symptoms related to blast crisis and leukostasis. Making a timely diagnosis and consulting a hematologist can be life saving. Presenting symptoms are caused by complications of bone marrow infiltration and hyperleukocytosis with white blood cell counts over 100,000. Presentations may include fatigue (anemia), bleeding (thrombocytopenia), shortness of breath, and/or neurologic symptoms owing to hyperleukocytosis and subsequent leukostasis. Treatment of symptomatic cases involves induction chemotherapy and/or leukapheresis. Asymptomatic hyperleukocytosis can be treated with hydroxyurea.


Subject(s)
Blast Crisis/etiology , Leukapheresis/methods , Leukostasis/complications , Blast Crisis/therapy , Chronic Disease , Humans , Leukostasis/therapy , Male , Middle Aged , Syndrome
8.
Respir Investig ; 55(2): 181-183, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28274536

ABSTRACT

A 59-year-old woman with epidermal growth factor receptor gene (EGFR) mutation-positive advanced lung adenocarcinoma was treated with afatinib after a diagnosis of chronic myelomonocytic leukemia (CMML). Twenty-one weeks later, she developed agranulocytosis, and CMML subsequently progressed to blast crisis. After complete remission of CMML, gefitinib was initiated; however, agranulocytosis recurred. This is the first reported case of both EGFR mutation-positive advanced non-small cell lung cancer with CMML, and of CMML blast crisis. Physicians should be aware of such risks and monitor EGFR-TKI-treated patients with myeloid neoplasms accordingly.


Subject(s)
Blast Crisis/drug therapy , Blast Crisis/etiology , Carcinoma, Non-Small-Cell Lung/drug therapy , Leukemia, Myelomonocytic, Chronic/drug therapy , Leukemia, Myelomonocytic, Chronic/pathology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Afatinib , Agranulocytosis/etiology , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/genetics , Female , Gefitinib , Genes, erbB-1/genetics , Humans , Leukemia, Myelomonocytic, Chronic/complications , Lung Neoplasms/complications , Lung Neoplasms/genetics , Middle Aged , Mutation , Protein Kinase Inhibitors/adverse effects , Quinazolines/adverse effects
9.
J Exp Med ; 214(2): 359-380, 2017 02.
Article in English | MEDLINE | ID: mdl-28031480

ABSTRACT

Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.


Subject(s)
Blast Crisis/etiology , CD27 Ligand/physiology , Leukemia, Myeloid, Acute/pathology , Signal Transduction/physiology , Tumor Necrosis Factor Receptor Superfamily, Member 7/physiology , Aged , Animals , Antibodies, Monoclonal/therapeutic use , CD27 Ligand/antagonists & inhibitors , Germinal Center Kinases , Humans , Leukemia, Myeloid, Acute/drug therapy , Mice , Middle Aged , Protein Serine-Threonine Kinases/physiology , TNF Receptor-Associated Factor 2/physiology , Tumor Cells, Cultured , Tumor Necrosis Factor Receptor Superfamily, Member 7/antagonists & inhibitors , Tumor Necrosis Factor Receptor Superfamily, Member 7/blood , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Wnt Signaling Pathway/physiology
10.
Leukemia ; 30(6): 1282-9, 2016 06.
Article in English | MEDLINE | ID: mdl-27012864

ABSTRACT

Blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), but its molecular basis remains poorly understood. Here, we show that CML BC is regulated by calcium-calmodulin-dependent kinase IIγ (CaMKIIγ). Genetic deletion of CaMKIIγ greatly inhibits disease progression via selectively impairing the self-renewal of leukemia stem cells (LSCs) in mouse models, whereas overexpression of CaMKIIγ has the opposite effects. In human CML, phosphorylated CaMKIIγ abundance is significantly associated with BC. Moreover, CaMKIIγ phosphorylates and reduces the nuclear cyclin-dependent kinase inhibitor p27Kip1, a critical brake that maintains LSC quiescence. These findings suggest that CaMKIIγ might be an important switch for the transition of CML BC and identify a unique mechanism by which CaMKIIγ promotes the self-renewal of LSCs by deceasing nuclear p27Kip1 to wake up dormant LSCs. Therefore, CaMKIIγ may provide a new therapeutic target to treat CML BC.


Subject(s)
Blast Crisis/etiology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/physiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Animals , Blast Crisis/pathology , Cell Self Renewal , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Heterografts , Humans , Mice , Neoplastic Stem Cells , Phosphorylation
11.
Leukemia ; 30(7): 1502-9, 2016 07.
Article in English | MEDLINE | ID: mdl-26984787

ABSTRACT

Chronic myeloid leukemia (CML) is characterized by expression of Bcr-abl, a tyrosine kinase oncogene. Clinical outcomes in CML were revolutionized by development of Bcr-abl-targeted tyrosine kinase inhibitors (TKIs), but CML is not cured by these agents. CML leukemia stem cells (LSCs) are relatively TKI insensitive and persist even in remission. LSC persistence results in relapse upon TKI discontinuation, or drug resistance or blast crisis (BC) during prolonged treatment. We hypothesize that increased expression of Fas-associated phosphatase 1 (Fap1) in CML contributes to LSC persistence and BC. As Fap1 substrates include Fas and glycogen synthase kinase-3ß (Gsk3ß), increased Fap1 activity in CML is anticipated to induce Fas resistance and stabilization of ß-catenin protein. Resistance to Fas-induced apoptosis may contribute to CML LSC persistence, and ß-catenin activity increases during BC. In the current study, we directly tested the role of Fap1 in CML LSC persistence using in an in vivo murine model. In TKI-treated mice, we found that inhibiting Fap1, using a tripeptide or small molecule, prevented TKI resistance, BC and relapse after TKI discontinuation; all events observed with TKI alone. In addition, Fap1 inhibition increased Fas sensitivity and decreased ß-catenin activity in CD34(+) bone marrow cells from human subjects with CML. Therapeutic Fap1 inhibition may permit TKI discontinuation and delay in progression in CML.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Tyrosine Phosphatase, Non-Receptor Type 13/physiology , Animals , Apoptosis/drug effects , Blast Crisis/etiology , Blast Crisis/pathology , Drug Resistance, Neoplasm/drug effects , Humans , Mice , Neoplastic Stem Cells/pathology , PDZ Domains , Protein Binding/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Tyrosine Phosphatase, Non-Receptor Type 13/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 13/metabolism , Recurrence , fas Receptor/metabolism
12.
J Ayub Med Coll Abbottabad ; 27(2): 371-4, 2015.
Article in English | MEDLINE | ID: mdl-26411119

ABSTRACT

BACKGROUND: Chronic myelogenous leukaemia (CML) is a hematopoietic stem cell disease with a relatively stable clinical course. Survival has increased with addition of Tyrosine Kinase inhibitors (TKI's). Its conversion into blast crises (BC) heralds an accelerated clinical course that is less responsive to treatment and has high mortality. METHODS: Clinical records of 20 patients with CML who transformed to BC in two years between January 2012 and December 2013 were reviewed. RESULTS: Out of total 240 patients, 20 (8.3%) transformed to blast crisis; among them 75% were males and 25% females. Mean age was 37.9 years (24-58 years) and 19 patients were positive for t (9; 22) (q34; q11) translocation at the time of transformation. The mean initial blood cell count was 204 (range: 33 to 526). Imatinib was offered in 76% of patients. The average duration between diagnosis and transformation to blast crises was 201 days (range: 24-333 days). Eight patients (40%) were transformed to acute myeloid leukaemia (AML) and 12 (60%) had acute lymphoblastic leukaemia (ALL). These patients were treated with standard AML/ALL type induction chemotherapy except one who died early. During the study period, 11 patients died. Median survival for whole group was 55 days. On bivariate and multivariate linear regression analyses mortality was not, significantly associated with the duration between diagnosis and development of blast crises or the type of treatment received. CONCLUSION: Treatment of BC remains a challenge, particularly in under resourced areas where allogeneic hematopoietic stem cell transplantation (Allo-SCT) facility is sparse. Outcomes remain dismal in majority of these patients.


Subject(s)
Benzamides/therapeutic use , Blast Crisis/mortality , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Agents/therapeutic use , Blast Crisis/etiology , Female , Humans , Imatinib Mesylate , Incidence , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Male , Middle Aged , Pakistan/epidemiology , Retrospective Studies , Survival Rate/trends
13.
Ann Hematol ; 94 Suppl 2: S159-65, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25814082

ABSTRACT

Due to the high efficacy of BCR-ABL tyrosine kinase inhibition (TKI) in chronic phase (CP) chronic myeloid leukemia (CML), the frequency of blast crisis (BC) is greatly reduced compared to the pre-TKI era. However, TKI treatment of BC has only marginally improved the number of favorable responses, including remissions, which for the most part have only been transitory. Occasionally, they provide a therapeutic window to perform an allogeneic stem cell transplantation (allo-SCT). The challenge remains to improve management of BC with the limited options available. We review and summarize articles pertaining to the treatment of BC CML published after 2002. Additionally, we will discuss whether there is a need for a new definition of BC and/or treatment failure.


Subject(s)
Blast Crisis/prevention & control , Hematopoietic Stem Cell Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Precision Medicine , Antineoplastic Agents/therapeutic use , Blast Crisis/diagnosis , Blast Crisis/etiology , Combined Modality Therapy , Disease Progression , Fusion Proteins, bcr-abl/antagonists & inhibitors , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/physiopathology , Practice Guidelines as Topic , Prognosis , Protein Kinase Inhibitors/therapeutic use , Recurrence , Transplantation, Homologous
14.
Leuk Lymphoma ; 55(7): 1451-62, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24050507

ABSTRACT

Despite vast improvements in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Blast Crisis/diagnosis , Blast Crisis/etiology , Blast Crisis/therapy , Disease Management , Disease Progression , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemia, Myeloid, Accelerated Phase/diagnosis , Leukemia, Myeloid, Accelerated Phase/drug therapy , Leukemia, Myeloid, Accelerated Phase/etiology , Neoplasm Staging , Prognosis , Treatment Outcome
15.
Proc Natl Acad Sci U S A ; 110(3): 1041-6, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23275297

ABSTRACT

The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole-transcriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3ß implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.


Subject(s)
Adenosine Deaminase/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Adenosine Deaminase/genetics , Alternative Splicing , Animals , Blast Crisis/etiology , Blast Crisis/genetics , Blast Crisis/metabolism , Blast Crisis/pathology , Cell Transformation, Neoplastic , Disease Progression , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Gene Knockdown Techniques , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Inflammation Mediators/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Chronic-Phase/genetics , Leukemia, Myeloid, Chronic-Phase/metabolism , Leukemia, Myeloid, Chronic-Phase/pathology , Mice , RNA Editing , RNA-Binding Proteins , Transcriptome , Transplantation, Heterologous , Tumor Stem Cell Assay
16.
Am J Hematol ; 86(12): 974-9, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21953568

ABSTRACT

Myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These disorders may undergo phenotypic shifts, and may specifically evolve into secondary myelofibrosis (MF) or acute myeloid leukemia (AML). We studied genomic changes associated with these transformations in 29 patients who had serial samples collected in different phases of disease. Genomic DNA from granulocytes, i.e., the myeloproliferative genome, was processed and hybridized to genome-wide human SNP 6.0 arrays. Most patients in chronic phase had chromosomal regions with uniparental disomy (UPD) and/or copy number changes. Disease progression to secondary MF or AML was associated with the acquisition of additional chromosomal aberrations in granulocytes (P = 0.002). A close relationship was observed between aberrations of chromosome 9p (UPD and/or gain) and progression from PV to post-PV MF (P = 0.002). The acquisition of one or more aberrations involving chromosome 5, 7, or 17p was specifically associated with progression to AML (OR 5.9, 95% CI 1.2-27.7, P = 0.006), and significantly affected overall survival (HR 18, 95% CI 1.9-164, P = 0.01). These observations indicate that disease progression from chronic-phase MPN to secondary MF or AML is associated with specific chromosomal aberrations that can be detected by means of high-resolution SNP array analysis of granulocyte DNA.


Subject(s)
Cell Transformation, Neoplastic/genetics , Chromosome Aberrations , Myeloproliferative Disorders/genetics , Polymorphism, Single Nucleotide , Blast Crisis/etiology , Blast Crisis/genetics , Blast Crisis/metabolism , DNA/chemistry , DNA/metabolism , Disease Progression , Female , Genome-Wide Association Study , Granulocytes/metabolism , Humans , Italy , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Leukemia, Myeloid/genetics , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/physiopathology , Male , Mutation , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/pathology , Myeloproliferative Disorders/physiopathology , Oligonucleotide Array Sequence Analysis , Polycythemia Vera/etiology , Polycythemia Vera/genetics , Polycythemia Vera/metabolism , Primary Myelofibrosis/etiology , Primary Myelofibrosis/genetics , Primary Myelofibrosis/metabolism , Receptors, Thrombopoietin/genetics , Receptors, Thrombopoietin/metabolism , Survival Analysis , Thrombocythemia, Essential/etiology , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/metabolism
17.
Cancer Sci ; 102(4): 784-91, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21205094

ABSTRACT

Mice deficient for Spa-1 encoding Rap GTPase-activating protein develop myeloproliferative disorder (MPD) of late onset with frequent blast crises. The mechanisms for MPD development as well as the reasons for long latency, however, remain elusive. We demonstrate here that preleukemic, disease-free Spa-1(-/-) mice show reduced steady-state hematopoiesis and attenuated resistance to whole body γ-ray irradiation, which are attributable to the sustained p53 response in hematopoietic progenitor cells (HPCs). Preleukemic Spa-1(-/-) HPCs show c-Myc overexpression with increased p19Arf as well as enhanced γH2AX expression with activation of Atm/Chk pathway. We also show that deregulated Rap signaling in the absence of Spa-1 enhances post-transcriptional c-Myc stability and induces DNA damage in a p38MAPK-dependent manner, leading to p53 activation. Genetic studies indicate that the introduction of p53(+/-) and p53(-/-) mutations in Spa-1(-/-) mice results in the acceleration of typical MPD and rapid development of blastic leukemia, respectively. These results suggest that increased c-Myc expression and DNA damage in HPCs precede MPD development in Spa-1(-/-) mice, and the resulting p53 response functions as a barrier for the onset of MPD and blast crises progression.


Subject(s)
DNA Damage , GTPase-Activating Proteins/physiology , Hematopoietic Stem Cells/physiology , Myeloproliferative Disorders/etiology , Nuclear Proteins/physiology , Proto-Oncogene Proteins c-myc/metabolism , Animals , Blast Crisis/etiology , Blast Crisis/metabolism , Blast Crisis/pathology , Blotting, Western , Flow Cytometry , Gamma Rays , Hematopoiesis , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation/genetics , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/pathology , Proto-Oncogene Proteins c-myc/genetics , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Survival Rate , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Whole-Body Irradiation , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism , rap1 GTP-Binding Proteins/genetics , rap1 GTP-Binding Proteins/metabolism
18.
Mali Med ; 25(1): 22-7, 2010.
Article in French | MEDLINE | ID: mdl-21436004

ABSTRACT

CONTEXT: Ten years after the use of alpha interferon in chronic myelogenous (CML) leukaemia treatment, we review this treatment. OBJECTIVE: We propose through this study to evaluate the therapeutic answer of the patients reached of CML in chronic phase and to study its impact on survival. MATERIAL AND METHODS: To be done we carried out a descriptive and analytical retrospective study concerning 40 patients carrying Chronic Myelogenous Leukaemia. RESULTS: The average age was 39.05 years and ratio sex was 0.9. 60% of the patients profited from the arm Hydroxyurea + Interferon alpha + Cytosine Arabinoside and 40% from Hydroxyurea + Interferon. The complete haematological answer was observed in 85.5%. The cytogenetic answer was documented only for two cases, and it acted of complete answer. On the evolutionary level, it was noted 27.5% of deaths related to a blastic transformation. The side effects were marked by occurred of alopecia, herpes and the gripal syndrome. The median of survival observed was 68.233 months or 5.68 years. The age, socioeconomic level, delay of treatment started, therapeutic protocol, length and regularity of treatment influenced the therapeutic response. CONCLUSION: Many factors influence the treatment response.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Blast Crisis/etiology , Cytarabine/administration & dosage , Female , Fusion Proteins, bcr-abl/blood , Humans , Hydroxyurea/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Kaplan-Meier Estimate , Leukemia, Myeloid, Chronic-Phase/genetics , Male , Middle Aged , Remission Induction , Retrospective Studies , Socioeconomic Factors , Virus Activation , Young Adult
19.
Am J Hematol ; 84(10): 641-4, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19691103

ABSTRACT

Blast phase (BP) may occur as a late event in essential thrombocythemia (ET). This study includes 19 patients with post-ET BP diagnosed and followed in a single institution. At BP, 63% of patients had leukocytosis (white blood cell count >10 x 10(9)/L), 74% had anemia (hemoglobin value <10 g/dL), 74% had thrombocytopenia (platelet count <100 x 10(9)/L), and 84% were over 65 years of age. Cytogenetic analysis was available in 10 patients: six had karyotype aberrations. According to cytogenetic-based risk stratification of de novo acute leukemia (AL), all patients had an unfavorable profile. JAK2 (V617F) mutational status was evaluated in five patients. In two of them, the JAK2 mutation was undetectable in blast cells (one with JAK2-positive ET), whereas in three both granulocytes and blast cells displayed the mutation. Treatment of BP was patient-based according to the performance status and co-morbidities and consisted of palliation in 14 patients, and of induction of remission in five. Median survival was 2.3 months (range 0.2-22.3), irrespective of the treatment received. In conclusion, this study indicates that AL evolved from ET has unfavorable clinical and biological features. JAK2 (V617F)-positive ET may evolve in few instances into JAK2-negative leukemia. The outcome of patients is poor whatever the treatment used.


Subject(s)
Blast Crisis/etiology , Thrombocythemia, Essential/complications , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blast Crisis/blood , Blast Crisis/drug therapy , Blast Crisis/epidemiology , Blood Platelets/cytology , Disease-Free Survival , Female , Hemoglobins/analysis , Humans , Janus Kinase 2/genetics , Leukocyte Count , Leukocytes/cytology , Male , Middle Aged , Mutation , Platelet Count , Risk Factors , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/epidemiology , Thrombocythemia, Essential/genetics
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